It is estimated that over 100 million Americans suffer from chronic pain at an annual cost to our society of over 500 billion dollars. For centuries, opioid drugs such as morphine have been the first-line treatment for severe pain. However, over time tolerance to opioid analgesia develops. Patients face increased risk as well as suffering when opioids lose effectiveness. In this proposal I describe our groundbreaking discovery that the clinically used epidermal growth factor receptor (EGFR; ErbB1) antagonist gefitinib (Iressa) completely reverses morphine tolerance. Based on our findings, we hypothesize that: 1) ErbB signaling is necessary and sufficient to cause morphine tolerance; 2) Chronic opioid administration increases ErbB signaling and may underlie the phenomenon of incomplete cross tolerance; 3) Chronic opioid administration differentially regulates ErbB expression and co-localization in the dorsal root ganglion and substantia gelatinosa; and 4) Opioid-induced ErbB signaling outputs are determined by a tightly regulated transcriptional network. We will test these hypotheses by performing studies with the following Specific Aims: 1) Define the mechanisms by which ErbB receptor signaling mediates opioid tolerance; 2) Determine the effects of opioid tolerance on ErbB signaling and whether ErbB signaling can explain incomplete cross tolerance; 3) Define the specific cellular subtypes expressing ErbB receptors in the dorsal root ganglion and dorsal horn of the spinal cord, and determine if their anatomic relationships are altered by chronic opioid administration; and 4) Determine the regulation of ErbB signaling responses induced by opioids, and begin to define the network structure that underlies these responses. These studies should dramatically improve our understanding of the molecular mechanisms underlying opioid tolerance. They also may lead to a completely new approach for the treatment of chronic pain. Our findings have the potential to dramatically reduce human suffering and improve the quality of life for untold millions of patients suffering from intractable pain.